Alzheimer's disease is characterized by two pathological hallmarks, namely extracellular accumulation of plaques, which are aggregates of amyloid beta (Aβ) peptides derived from proteolytic cleavages of amyloid precursor protein (APP), and intracellular accumulation of hyperphosphorylated tau (Hardy & Selkoe (2002) Science 297:353-356). APP can be cleaved via two competing pathways, the alpha and the beta secretase pathways, which are distinguished by different subcellular sites of proteolysis and cleavage points within APP (Thinakaran & Koo (2008) J. Biol. Chem. 283:29615-29619). Several proteases are capable of producing the alpha-cleavage, after which the gamma-secretase complex that includes presenilin 1 as a catalytic subunit, further cleaves the APP fragment to produce small, non-amyloidogenic fragments. The beta-secretase pathway involves sequential cleavages by beta-secretase and gamma-secretase complexes, and generates Aβ. APP and secretases are all membrane bound proteins/enzymes. Studies have shown that cholesterol content in cells can affect the production of Aβ, in part by the ability of cholesterol to modulate the enzyme activities of various secretases in cell membranes (Wolozin (2004) Neuron 41:7-10). Cholesterol metabolism has also been implicated in the pathogenesis of Alzheimer's disease in other manners (Jiang, et al. (2008) Neuron 58:681-693; Wellington (2004) Clin. Genet. 66:1-16; Hartmann (2001) Trends Neurosci. 24:S45-48).
In the brain, cholesterol is derived from endogenous biosynthesis (Dietschy & Turley (2004) J. Lipid Res. 45:1375-1397). The transcription factor SREBP2 controls the expression of enzymes involved in cholesterol biosynthesis, including the rate-limiting enzyme HMG-CoA reductase (HMGR) (Goldstein, et al. (2006) Cell 124:35-46). Other transcription factors, including liver X receptors (LXRs), control the expression of proteins which function in cholesterol transport (Repa & Mangelsdorf (2000) Annu. Rev. Cell Dev. Biol. 16:459-481; Beaven & Tontonoz (2006) Annu. Rev. Med. 57:313-329), including apoE, ABCA1, and others (Wang, et al. (2008) FASEB J. 22:1073-1082; Tarr & Edwards (2008) J. Lipid Res. 49:169-182). In the brain, cholesterol can be enzymatically converted by a brain-specific enzyme, 24-hydroxylase (CYP46A1) (Russell, et al. (2009) Annu. Rev. Biochem. 78:1017-1040), to an oxysterol called 24S-hydroxycholesterol (24SOH); the concentration of 24SOH far exceeds those of other oxysterols in the brain (Lutjohann, et al. (1996) Proc. Natl. Acad. Sci. USA 93:9799-9804 Bjorkhem (2006) J. Intern. Med. 260:493-508; Karu, et al. (2007) J. Lipid Res. 48:976-987). Various oxysterols, including 24SOH, can down-regulate sterol synthesis in intact cells and in vitro (Song, et al. (2005) Cell Metab. 1:179-189; Wang, et al. (2008) J. Proteome Res. 7:1606-1614). When provided to neurons, 24SOH decreases the secretion of Aβ (Brown, et al. (2004) J. Biol. Chem. 279:34674-34681). However, whether 24SOH or other oxysterols can act in similar fashion(s) in vivo remains to be demonstrated. 24SOH levels have been shown to be decreased in brain samples from Alzheimer's disease patients (Heverin, et al. (2004) J. Lipid Res. 45:186-193), suggesting a relationship between 24SOH and Alzheimer's disease.
Acyl-CoA:Cholesterol Acyltransferase (ACAT) converts free cholesterol to cholesterol ester, and is one of the key enzymes in cellular cholesterol metabolism. Two ACAT genes have been identified which encode two different enzymes, ACAT1 and ACAT2 (also known as SOAT1 and SOAT2). While both ACAT1 and ACAT2 are present in the liver and intestine, the cells containing either enzyme within these tissues are distinct, suggesting that ACAT1 and ACAT2 have separate functions. Both enzymes are potential drug targets for treating dyslipidemia and atherosclerosis.
Using the non-selective ACAT inhibitor, CP-113,818 (Chang et al. (2000) J. Biol. Chem. 275:28083-28092), Alzheimer's disease-like pathology in the brains of transgenic mice expressing human APP(751) containing the London (V717I) and Swedish (K670M/N671L) mutations has been demonstrated (Hutter-Paier, et al. (2004) Neuron. 44(2):227-38). Two months of treatment with CP-113,818 was shown to reduce the accumulation of amyloid plaques by 88%-99% and membrane/insoluble Amyloid β levels by 83%-96%, while also decreasing brain cholesteryl-esters by 86%. Additionally, soluble Amyloid β(42) was reduced by 34% in brain homogenates. Spatial learning was slightly improved and correlated with decreased Amyloid β levels. In nontransgenic littermates, CP-113,818 also reduced ectodomain shedding of endogenous APP in the brain.
A 50% decrease in ACAT1 expression has also been shown to reduce cholesteryl ester levels by 22%, reduce proteolytic processing of APP, and decrease Amyloid β secretion by 40% (Huttunen, et al. (2007) FEBS Lett. 581(8):1688-92) in an in vitro neuronal cell line. In this regard, it has been suggested that ACAT inhibition could serve as a strategy to treat Alzheimer's disease (Huttunen & Kovacs (2008) Neurodegener. Dis. 5(3-4):212-4).